Regulation of Neutrophilic Lung Inflammation

中性粒细胞性肺部炎症的调节

• 批准号: 7791017
• 负责人: John W Christman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791017
• 关键词: Address; Adult Respiratory Distress Syndrome; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; B-Lymphocytes; Binding; Bone Marrow; Breathing; Cells; Chimera organism; Data; Distal; Endotoxins; Enzymes; Event; Funding; Gene Expression; Gene Expression Regulation; Generations; Health; In Vitro; Inflammation; Inflammatory; Intensive Care Units; Isomerase; Laboratories; Lead; Life; Lung; Lung Inflammation; Lung diseases; MAP Kinase Kinase Kinase; Mechanics; Mediating; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; NF-kappa B; NF-kappaB-inducing kinase; Nuclear; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Phosphotransferases; Physiological; Play; Production; Property; Prostaglandin D2; Prostaglandins; Proteins; Regulation; Relative (related person); Research; Resolution; Role; Sepsis; Serine; Stimulus; Supportive care; Survival Rate; Therapeutic; Time; Work; abstracting; attenuation; base; chemokine; cyclooxygenase 2; cyclopentanone; cytokine; design; effective therapy; lipocalin 1; lung injury; macrophage; mortality; neutrophil; novel; novel strategies; prostaglandin R2 D-isomerase; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Abstract: The acute respiratory distress syndrome (ARDS) associated with severe sepsis is a neutrophilic inflammatory lung disease (NLI) with excessive morbidity and mortality. In spite of improvements in supportive care that have resulted in better survival rates, there are no effective specific treatments of ARDS that are based on the molecular pathogenesis. We propose to investigate the pre-transcriptional events in pulmonary macrophages that lead to cytokine- and chemokine-mediated inflammation in the lung. In previous years of funding, we have focused on the early effects of NADPH oxidase that result in attenuation of the NF-:B activation pathway. We now propose to investigate the role of NADPH oxidase in the resolution of neutrophilic lung inflammation in pulmonary macrophages. We will consider the effects of NADPH oxidase on gene regulation of cyclooxygenase-2 (COX-2) and lipocalin-prostaglandin D synthase (L-PgDS) gene expression which results in relative increase in prostaglandin D2 (PgD2) and on activation of nuclear factor E2 p45-related factor 2 (Nrf2). Degradation products of PgD2, called cyclopentanones, have potent anti-inflammatory properties and Nrf2 has a role in gene regulation of anti-oxidant and detoxifying proteins that are protective. Our laboratory has identified a novel pathway by which a redox sensitive kinase, NF-:B inducing kinase (NIK), regulates gene expression L-PgDS and production of PgD2 through phosphorylation of PU.1, a macrophage specific transcription factor. In this proposal, we hypothesize that NADPH oxidase generated ROS in pulmonary macrophages has a dual role in mediating neutrophiilc lung inflammation. In early neutrophilc lung inflammation, ROS contributes to activation of NF-:B and generation of cytokine, chemokine, and cyclooxygenase-2 (COX-2) gene expression. However, at later time points, which will be the focus of this proposal, NADPH oxidase- generated ROS mediates resolution of neutrophilc lung inflammation through effects on the production of anti-inflammatory prostanoids and anti-oxidants and detoxifying proteins regulated by Nrf2. We propose two specific aim: 1: To determine the necessity of macrophage NADPH oxidase generated ROS on resolution of neutrophil lung inflammation in response to treatment with endotoxin and 2: To determine the requirement of macrophage NADPH oxidase generated ROS in redox regulation of NIK and Nrf2 activation and to determine the consequences of NIK and Nrf2 activation on the resolution of NLI. By examining the physiological role of NADPH oxidase on the resolution of neutrophilc lung inflammation, we expect to identify novel mechanisms that could provide evidence for effective therapeutic approaches to limit lung injury and restore health in patients suffering from ARDS and other inflammation lung diseases. PUBLIC HEALTH RELEVANCE: Project Narrative: The acute respiratory distress syndrome (ARDS) is a severe and life threatening condition that requires a mechanical breathing machine and other supportive care in an intensive care unit. We have shown that macrophages in the lung have an essential role in initiating the severe lung inflammation that causes ARDS. The purpose of this research is to define the basic molecular mechanisms that regulate macrophage involvement in ARDS in order to design new and effective treatments.

描述（由申请人提供）： 摘要：与严重败血症相关的急性呼吸窘迫综合征（ARDS）是一种嗜中性炎症性肺部疾病（NLI），发病率过高和死亡率。尽管支持护理的改善导致了更好的存活率，但没有基于分子发病机理的ARD的有效特定治疗方法。我们建议研究导致肺部因子和趋化因子介导的肺部炎症的肺巨噬细胞中的转录前事件。在资金的往年，我们专注于NADPH氧化酶的早期作用，从而导致NF-：B激活途径的衰减。现在，我们建议研究NADPH氧化酶在肺巨噬细胞中嗜中性肺炎症的分辨率中的作用。我们将考虑NADPH氧化酶对环氧酶-2（COX-2）和Lipocalin-prostaglandin D合酶（L-PGDS）基因表达的基因调节的影响，从而导致前列腺素D2（PGD2）的相对增加以及核因子E2 P45-P45-pelated因子2（NRF2）的激活。 PGD​​2的降解产物（称为环戊酮）具有有效的抗炎特性，而NRF2在抗氧化剂和抗毒蛋白的基因调节中起作用。我们的实验室已经确定了一种新的途径，氧化还原敏感的激酶NF-：B诱导激酶（NIK），调节基因表达L-PGD和PGD2通过PU.1的磷酸化（一种巨噬细胞特异性转录因子）的磷酸化。在此提案中，我们假设NADPH氧化酶在肺巨噬细胞中产生ROS在介导嗜中性粒细胞性肺炎症中具有双重作用。在早期嗜中性粒细胞炎症中，ROS有助于NF-：B的激活以及细胞因子，趋化因子和环氧酶-2（COX-2）基因表达的生成。然而，在以后的时间点（这将是该提案的重点），NADPH氧化酶产生的ROS通过对抗炎前列腺素的产生和抗氧化剂和抗氧化剂的产生以及由NRF2调节的抗氧化剂和解毒蛋白的产生，从而介导了中性粒细胞肺炎症的分辨率。我们提出了两个具体的目的：1：确定巨噬细胞NADPH氧化酶的必要性，在嗜中性粒细胞炎症的分辨率上产生ROS，响应于内毒素和2：2：确定巨噬细胞NADPH氧化酶在NIK和NRF2激活中的氧化还能调节中产生的ROS的需求，以确定NIK和NIK nik nik 2激活的结果。通过检查NADPH氧化酶对嗜中性粒细胞肺炎症的分辨率的生理作用，我们希望确定新的机制，这些机制可以为有效的治疗方法提供限制肺损伤并恢复患有ARDS和其他炎症肺部疾病的患者的健康的证据。 公共卫生相关性： 项目叙述：急性呼吸窘迫综合征（ARDS）是一种严重且威胁生命的疾病，需要机械呼吸机和重症监护病房的其他支持护理。我们已经表明，肺中的巨噬细胞在引发引起ARD的严重肺部炎症中起着至关重要的作用。这项研究的目的是定义调节巨噬细胞参与ARD的基本分子机制，以设计新的和有效的治疗方法。